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Mechanisms of Endocrine and Molecular Bone Regulation

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (15 December 2022) | Viewed by 14248

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Prof. Dr. Jean Pierre Salles

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Guest Editor

CHU de Toulouse, INSERM UMR 1043 CNCRS 5828 (CPTP), University of Toulouse, Toulouse, France
Interests: mechanisms of endocrine and bone regulation; rare endocrine and bone diseases; molecular signaling of hormones; regulation of calcium metabolism; Prader–Willi syndrome pathophysiology

Prof. Dr. Agnes Linglart

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Co-Guest Editor

1. AP-HP, endocrinology and diabetes for children, Paris-Saclay Hospital, Le Kremlin Bicêtre, France
2. Université Paris-Saclay, INSERM, Physiologie et Physiopathologie Endocriniennes, Le Kremlin-Bicêtre, France
Interests: pediatric endocrinology; bone; calcium and phosphate metabolism; growth

Special Issue Information

Dear Colleagues,

Bone regulation offers striking new opportunities for its better understanding. Integration between molecular and endocrine mechanisms reveals unexpected relationships. Discovery of new agents involved in bone development has opened wide perspectives for the physiology and treatment of bone diseases and osteoporosis. Systemic regulation of bone mass by hormones such as growth hormone and IGF1, sex steroids, but also neuroendocrine hormones like leptin, ghrelin, oxytocin or other putative regulators during development and beyond is prominent. New actors such as FGF23 have appeared. The control of bone mass under recruitment and differentiation of osteoblasts precursors, as well as the role of osteocyte under mechanic stimulation, remain a still largely unexplored area. Local paracrine regulators, namely linked to the sclerostin pathway, seem also prominent. The goal is to provide an integrative vision of the main systemic and local regulators of bone mass, with special regard to new therapeutic options.

Prof. Dr. Jean Pierre Salles
Prof. Agnes Linglart
Guest Editors

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Keywords

Bone mass
IGF1
Growth hormone
FGF23
Oxytocin
Leptin
Osteoblast
Osteocyte
GNAS
ALPL
PPi
Sclerostin

Published Papers (5 papers)

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Research

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18 pages, 2551 KiB

Open AccessArticle

11β-Hydroxysteroid Dehydrogenase Type 1 within Osteoclasts Mediates the Bone Protective Properties of Therapeutic Corticosteroids in Chronic Inflammation

by Chloe G Fenton, Ana Crastin, Claire S Martin, Saicharan Suresh, Isabella Montagna, Bismah Hussain, Amy J Naylor, Simon W Jones, Morten S Hansen, Caroline M Gorvin, Maria Price, Andrew Filer, Mark S Cooper, Gareth G Lavery, Karim Raza and Rowan S Hardy

Int. J. Mol. Sci. 2022, 23(13), 7334; https://doi.org/10.3390/ijms23137334 - 30 Jun 2022

Cited by 4 | Viewed by 3132

Abstract

Therapeutic glucocorticoids (GCs) are powerful anti-inflammatory tools in the management of chronic inflammatory diseases such as rheumatoid arthritis (RA). However, their actions on bone in this context are complex. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a mediator of the anti-inflammatory actions of therapeutic glucocorticoids (GCs) in vivo. In this study we delineate the role of 11β-HSD1 in the effects of GC on bone during inflammatory polyarthritis. Its function was assessed in bone biopsies from patients with RA and osteoarthritis, and in primary osteoblasts and osteoclasts. Bone metabolism was assessed in the TNF-tg model of polyarthritis treated with oral GC (corticosterone), in animals with global (TNF-tg^11βKO), mesenchymal (including osteoblast) (TNF-tg^{11βflx/tw2cre}) and myeloid (including osteoclast) (TNF-tg^{11βflx/LysMcre}) deletion. Bone parameters were assessed by micro-CT, static histomorphometry and serum metabolism markers. We observed a marked increase in 11β-HSD1 activity in bone in RA relative to osteoarthritis bone, whilst the pro-inflammatory cytokine TNFα upregulated 11β-HSD1 within osteoblasts and osteoclasts. In osteoclasts, 11β-HSD1 mediated the suppression of bone resorption by GCs. Whilst corticosterone prevented the inflammatory loss of trabecular bone in TNF-tg animals, counterparts with global deletion of 11β-HSD1 were resistant to these protective actions, characterised by increased osteoclastic bone resorption. Targeted deletion of 11β-HSD1 within osteoclasts and myeloid derived cells partially reproduced the GC resistant phenotype. These data reveal the critical role of 11β-HSD1 within bone and osteoclasts in mediating the suppression of inflammatory bone loss in response to therapeutic GCs in chronic inflammatory disease. Full article

(This article belongs to the Special Issue Mechanisms of Endocrine and Molecular Bone Regulation)

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24 pages, 3137 KiB

Open AccessArticle

Effect of Anti-Osteoporotic Treatments on Circulating and Bone MicroRNA Patterns in Osteopenic ZDF Rats

by David Carro Vázquez, Lejla Emini, Martina Rauner, Christine Hofbauer, Johannes Grillari, Andreas B. Diendorfer, Richard Eastell, Lorenz C. Hofbauer and Matthias Hackl

Int. J. Mol. Sci. 2022, 23(12), 6534; https://doi.org/10.3390/ijms23126534 - 10 Jun 2022

Cited by 1 | Viewed by 2521

Abstract

Bone fragility is an adverse outcome of type 2 diabetes mellitus (T2DM). The underlying molecular mechanisms have, however, remained largely unknown. MicroRNAs (miRNAs) are short non-coding RNAs that control gene expression in health and disease states. The aim of this study was to investigate the genome-wide regulation of miRNAs in T2DM bone disease by analyzing serum and bone tissue samples from a well-established rat model of T2DM, the Zucker Diabetic Fatty (ZDF) model. We performed small RNA-sequencing analysis to detect dysregulated miRNAs in the serum and ulna bone of the ZDF model under placebo and also under anti-sclerostin, PTH, and insulin treatments. The dysregulated circulating miRNAs were investigated for their cell-type enrichment to identify putative donor cells and were used to construct gene target networks. Our results show that unique sets of miRNAs are dysregulated in the serum (n = 12, FDR < 0.2) and bone tissue (n = 34, FDR < 0.2) of ZDF rats. Insulin treatment was found to induce a strong dysregulation of circulating miRNAs which are mainly involved in metabolism, thereby restoring seven circulating miRNAs in the ZDF model to normal levels. The effects of anti-sclerostin treatment on serum miRNA levels were weaker, but affected miRNAs were shown to be enriched in bone tissue. PTH treatment did not produce any effect on circulating or bone miRNAs in the ZDF rats. Altogether, this study provides the first comprehensive insights into the dysregulation of bone and serum miRNAs in the context of T2DM and the effect of insulin, PTH, and anti-sclerostin treatments on circulating miRNAs. Full article

(This article belongs to the Special Issue Mechanisms of Endocrine and Molecular Bone Regulation)

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11 pages, 1539 KiB

Open AccessArticle

ApoA1 Deficiency Reshapes the Phenotypic and Molecular Characteristics of Bone Marrow Adipocytes in Mice

by Afroditi Kastrenopoulou, Kyriakos E. Kypreos, Nicholaos I. Papachristou, Stavros Georgopoulos, Ioulia Mastora, Ioanna Papadimitriou-Olivgeri, Argyro Spentzopoulou, Dragana Nikitovic, Vassilios Kontogeorgakos, Harry C. Blair and Dionysios J. Papachristou

Int. J. Mol. Sci. 2022, 23(9), 4834; https://doi.org/10.3390/ijms23094834 - 27 Apr 2022

Cited by 5 | Viewed by 2020

Abstract

In the present study, we studied the effect of apolipoprotein A-1 (APOA1) on the spatial and molecular characteristics of bone marrow adipocytes, using well-characterized ApoA1 knockout mice. APOA1 is a central regulator of high-density lipoprotein cholesterol (HDL-C) metabolism, and thus HDL; our recent work showed that deficiency of APOA1 increases bone marrow adiposity in mice. We found that ApoA1 deficient mice have greatly elevated adipocytes within their bone marrow compared to wild type counterparts. Morphologically, the increased adipocytes were similar to white adipocytes, and displayed proximal tibial-end localization. Marrow adipocytes from wild type mice were significantly fewer and did not display a bone-end distribution pattern. The mRNA levels of the brown/beige adipocyte-specific markers Ucp1, Dio2, Pat2, and Pgc1a; and the expression of leptin were greatly reduced in the ApoA1 knock-out in comparison to the wild-type mice. In the knock-out mice, adiponectin was remarkably elevated. In keeping with the close ties of hematopoietic stem cells and marrow adipocytes, using flow cytometry we found that the elevated adiposity in the ApoA1 knockout mice is associated with a significant reduction in the compartments of hematopoietic stem cells and common myeloid, but not of the common lymphoid, progenitors. Moreover, the ‘beiging’-related marker osteopontin and the angiogenic factor VEGF were also reduced in the ApoA1 knock-out mice, further supporting the notion that APOA1—and most probably HDL-C—regulate bone marrow microenvironment, favoring beige/brown adipocyte characteristics. Full article

(This article belongs to the Special Issue Mechanisms of Endocrine and Molecular Bone Regulation)

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Review

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14 pages, 1709 KiB

Open AccessReview

Biological Activity of Different Forms of Oxidized Parathyroid Hormone

by Ahmed A. Hasan, Carl-Friedrich Hocher, Burkhard Kleuser, Bernhard K. Krämer and Berthold Hocher

Int. J. Mol. Sci. 2022, 23(20), 12228; https://doi.org/10.3390/ijms232012228 - 13 Oct 2022

Cited by 3 | Viewed by 1664

Abstract

Preclinical studies have shown that parathyroid hormone (PTH) loses its biological effects through oxidation. PTH can be oxidized at methionines 8 and 18. Three possible variations of oxidized PTH (oxPTH) exist: Met8(ox)PTH, Met18(ox)PTH, and Met8, Met18(di-ox)PTH. A recent study showed that Met18(ox)PTH retained biological activity and was able to upregulate Fgf23 gene expression, whereas Met8(ox)PTH and Met8, Met18(di-ox)PTH showed less or no biological activity. An earlier study likewise showed that the oxidation of Met18 has minor effects on the secondary structure of PTH, whereas the oxidation of Met8 causes substantial structural changes, consistent with another study showing that oxidization just at Met8 blocks the generation of the second messenger cAMP, whereas the effect of the oxidation of Met18 is much less potent in inhibiting cAMP formation. A considerable percentage of circulating PTH in chronic kidney disease (CKD) patients is oxidized. However, we do not know the relative amounts of the different forms of oxPTH with agonistic, partial agonistic, or even antagonistic biological actions in different CKD populations. This might explain different clinical findings in the different CKD populations analyzed so far. The currently available method that was used in these clinical studies just distinguishes between oxPTH and noxPTH without being able to differentiate between different forms of oxPTH. Only methods of PTH measurement that are able to differentiate between PTH forms (noxPTH, Met8(ox)PTH, Met18(ox)PTH, and Met8, Met18(di-ox)PTH) have the potential to improve patient care, because only these methods will definitively separate bioactive from non-bioactive PTH forms. Such methods need to be developed, validated, and used in prospective randomized clinical trials to define the potential value of bioactive PTH forms as a predictor of cardiovascular events, mortality, and bone turnover. Full article

(This article belongs to the Special Issue Mechanisms of Endocrine and Molecular Bone Regulation)

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19 pages, 2461 KiB

Open AccessReview

Sclerostin: From Molecule to Clinical Biomarker

by Ahmed Omran, Diana Atanasova, Filip Landgren and Per Magnusson

Int. J. Mol. Sci. 2022, 23(9), 4751; https://doi.org/10.3390/ijms23094751 - 26 Apr 2022

Cited by 9 | Viewed by 3984

Abstract

Sclerostin, a glycoprotein encoded by the SOST gene, is mainly produced by mature osteocytes and is a critical regulator of bone formation through its inhibitory effect on Wnt signaling. Osteocytes are differentiated osteoblasts that form a vast and highly complex communication network and orchestrate osteogenesis in response to both mechanical and hormonal cues. The three most commonly described pathways of SOST gene regulation are mechanotransduction, Wnt/β-catenin, and steroid signaling. Downregulation of SOST and thereby upregulation of local Wnt signaling is required for the osteogenic response to mechanical loading. This review covers recent findings concerning the identification of SOST, in vitro regulation of SOST gene expression, structural and functional properties of sclerostin, pathophysiology, biological variability, and recent assay developments for measuring circulating sclerostin. The three-dimensional structure of human sclerostin was generated with the AlphaFold Protein Structure Database applying a novel deep learning algorithm based on the amino acid sequence. The functional properties of the 3-loop conformation within the tertiary structure of sclerostin and molecular interaction with low-density lipoprotein receptor-related protein 6 (LRP6) are also reviewed. Second-generation immunoassays for intact/biointact sclerostin have recently been developed, which might overcome some of the reported methodological obstacles. Sclerostin assay standardization would be a long-term objective to overcome some of the problems with assay discrepancies. Besides the use of age- and sex-specific reference intervals for sclerostin, it is also pivotal to use assay-specific reference intervals since available immunoassays vary widely in their methodological characteristics. Full article

(This article belongs to the Special Issue Mechanisms of Endocrine and Molecular Bone Regulation)

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